# 1,2,4-Thiadiazolidin-3,5-Diones as Inhibitors of Cysteine Proteases

## TL;DR

This study explores a class of compounds that can both release hydrogen sulfide and inhibit key viral enzymes, suggesting potential for antiviral drug development.

## Contribution

The study identifies specific thiadiazolidin-diones as potent and selective inhibitors of SARS-CoV-2 proteases.

## Key findings

- THIA-6, -7, and -10 are the most potent inhibitors of SARS-CoV-2 3CLpro.
- THIA-1, -2, and -8 show the highest selectivity against other proteases.
- Computational studies support the compounds' inhibition mechanisms and guide future optimization.

## Abstract

A focused library of 1,2,4-thiadiazolidin-3,5-diones (THIA-1–10), previously characterized as hydrogen sulfide (H2S) donors, was evaluated for inhibitory activity against cysteine proteases. We included two key cysteine proteases aiming at antiviral drug development—SARS-CoV-2 3CLpro (Mpro) and PLpro—alongside reference enzymes Papain and Cathepsin L. The compounds exhibited distinct selectivity profiles and inhibition mechanisms. The ability to act as covalent inhibitors of 3CLpro in the nanomolar range is of particular interest, with compounds THIA-6, -7, and -10 proving to be the most potent inhibitors of the series, and compounds THIA-1, -2, and -8 proving to be the most selective with respect to the other proteases. We explored the molecular bases of the observed activity profile of THIA-1–10 through computational studies, which supported and complemented the experimental findings, paving the way for future structure optimization. The results highlight that inhibitory potency depends not only on electrophilicity but also on the ability to access the catalytic cysteine within the active site. The dual functionality of THIA-1–10 as H2S donors and selective cysteine protease inhibitors underscores its potential as a promising lead for therapeutic development.